Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK.
Inflamm Bowel Dis. 2013 Feb;19(2):259-64. doi: 10.1097/MIB.0b013e31828100a4.
Mucosal addressin cell-adhesion molecule (MAdCAM)-1, which is overexpressed on gut endothelium in active Crohn's disease (CD), promotes intestinal recruitment of integrin α(4)β(7)(*) T cells that sustain chronic inflammation. As tumor necrosis factor alpha (TNF)-α, a cytokine centrally involved in CD, modulates gut endothelial adhesion molecules, we here explored the in vivo and ex vivo effects of TNF-α blockade on MAdCAM-1 expression in CD.
MAdCAM-1 was determined by immunoblotting in colonic biopsies collected before and 10 weeks after either infliximab or adalimumab treatment in CD patients, and in CD biopsies incubated with either infliximab or adalimumab or control IgG(1). Integrin β(7)(*) circulating T cells were analyzed by flow cytometry.
MAdCAM-1 significantly decreased after either infliximab or adalimumab treatment in responder but not in nonresponder patients. In parallel, an increase of circulating β(7)(*) T cells was found in responder patients only. A marked downregulation of MAdCAM-1 was observed in CD biopsies cultured with either infliximab or adalimumab in comparison to IgG(1)-treated biopsies.
Our findings showing that MAdCAM-1 is downregulated by TNF-α blockade point to a novel mechanism of action of anti-TNF-α antibodies in CD.
黏附分子地址素细胞-1（MAdCAM-1）在活动性克罗恩病（CD）的肠道内皮细胞中过度表达，促进整合素α（4）β（7）（*）T 细胞在肠道中的募集，从而维持慢性炎症。由于肿瘤坏死因子-α（TNF-α）作为一种在 CD 中起核心作用的细胞因子，可调节肠道内皮细胞黏附分子，因此我们在此研究了 TNF-α 阻断对 CD 中 MAdCAM-1 表达的体内和体外影响。
通过免疫印迹法测定 CD 患者接受英夫利昔单抗或阿达木单抗治疗前和治疗 10 周后的结肠活检组织中 MAdCAM-1 的表达，并测定 CD 活检组织在接受英夫利昔单抗或阿达木单抗或对照 IgG（1）孵育后的 MAdCAM-1 表达。通过流式细胞术分析循环β（7）（*）T 细胞。
在应答者而非无应答者患者中，接受英夫利昔单抗或阿达木单抗治疗后 MAdCAM-1 显著降低。同时，仅在应答者患者中发现循环β（7）（*）T 细胞增加。与 IgG（1）处理的活检组织相比，在接受英夫利昔单抗或阿达木单抗培养的 CD 活检组织中，MAdCAM-1 明显下调。
我们的研究结果表明，MAdCAM-1 被 TNF-α 阻断下调，这为抗 TNF-α 抗体在 CD 中的作用机制提供了新的见解。
